Identification of interaction partners of outer inflammatory protein A: Computational and experimental insights into how Helicobacter pylori infects host cells.

Outer membrane proteins (OMPs) play a key role in facilitating the survival of Helicobacter pylori within the gastric tissue by mediating adherence. Among these proteins, Outer inflammatory protein A (OipA) is a critical factor in H. pylori colonization of the host gastric epithelial cell surface.

Rational design of monomeric IL37 variants guided by stability and dynamical analyses of IL37 dimers.

IL37 plays important roles in the regulation of innate immunity and its oligomeric status is critical to these roles. In its monomeric state, IL37 can effectively inhibit the inflammatory response of IL18 by binding to IL18R, a capacity lost in its dimeric form, underlining the pivotal role of the oligomeric status of IL37 in its anti-inflammatory action. Until now, two IL37 dimer structures have been deposited in PDB, reflecting a substantial difference in their dimer interfaces.

Computational completion of the Aurora interaction region of N-Myc in the Aurora a kinase complex.

Inhibiting protein-protein interactions of the Myc family is a viable pharmacological strategy for modulation of the levels of Myc oncoproteins in cancer. Aurora A kinase (AurA) and N-Myc interaction is one of the most attractive targets of this strategy because formation of this complex blocks proteasomal degradation of N-Myc in neuroblastoma. Two crystallization studies have captured this complex (PDB IDs: 5g1x, 7ztl), partially resolving the AurA interaction region (AIR) of N-Myc.

Effect of the switch status of Helicobacter pylori outer inflammatory protein A on gastric diseases.

Helicobacter pylori OipA (Outer Inflammatory Protein A) is an outer membrane protein that takes role in the adherence and colonization to the stomach. oipA gene expression is regulated by the slipped-strand mispairing mechanism through a hypermutable CT dinucleotide repeat motif in the 5΄ region. Alterations in the CT number repeats cause frame-shift mutations to result in phase variation of oipA expression.

A small non-interface surface epitope in human IL18 mediates the dynamics and self-assembly of IL18-IL18BP heterodimers.

Interleukin 18 (IL18) is a pro-inflammatory cytokine that modulates innate and adaptive immune responses. IL18 activity is tightly controlled by the constitutively secreted IL18 binding protein (IL18BP). PDB structures of human IL18 showed that a short stretch of amino acids between 68 and 81 adopted a disordered conformation in all IL18-IL18BP complexes while adopting a 3 helical structure in other IL18 structures, including the receptor complexes.

Follicular homocysteine as a marker of oocyte quality in PCOS and the role of micronutrients.

Purpose: Does follicular homocysteine predict the reproductive potential of oocytes following FSH stimulation in PCOS women? Can it be modulated by dietary interventions?

Methods: This was a prospective, randomized, interventional clinical study. Forty-eight PCOS women undergoing in vitro fertilization at a private fertility clinic were randomized for a dietary supplementation providing micronutrients involved in homocysteine clearance or no treatment. The supplement was assumed 2 months before stimulation until pick-up day.

Evaluation of AlphaFold structure-based protein stability prediction on missense variations in cancer.

Identifying pathogenic missense variants in hereditary cancer is critical to the efforts of patient surveillance and risk-reduction strategies. For this purpose, many different gene panels consisting of different number and/or set of genes are available and we are particularly interested in a panel of 26 genes with a varying degree of hereditary cancer risk consisting of , and In this study, we have compiled a collection of the missense variations reported in any of these 26 genes. More than a thousand missense variants were collected from ClinVar and the targeted screen of a breast cancer cohort of 355 patients which contributed to this set with 160 novel missense variations.

Brave new surfactant world revisited by thermoalkalophilic lipases: computational insights into the role of SDS as a substrate analog.

Non-ionic surfactants were shown to stabilize the active conformation of thermoalkalophilic lipases by mimicking the lipid substrate while the catalytic interactions formed by anionic surfactants have not been well characterized. In this study, we combined μs-scale molecular dynamics (MD) simulations and lipase activity assays to analyze the effect of ionic surfactant, sodium dodecyl sulfate (SDS), on the structure and activity of thermoalkalophilic lipases. Both the open and closed lipase conformations that differ in geometry were recruited to the MD analysis to provide a broader understanding of the molecular effect of SDS on the lipase structure.

Modeling and dynamical analysis of the full-length structure of factor XII with zinc.

Zinc (II), the second most abundant transition metal in blood, binds to the initiator of the contact pathway, factor XII (FXII). This binding induces conformational changes in the structure of FXII eventually leading to its activation. Despite many in vitro and in vivo studies on zinc-mediated activation of FXII, its molecular mechanism remains elusive mainly due to absence of a full-length structural model of FXII.

Toward Compilation of Balanced Protein Stability Data Sets: Flattening the ΔΔ Curve through Systematic Enrichment.

Often studies analyzing stability data sets and/or predictors ignore neutral mutations and use a binary classification scheme labeling only destabilizing and stabilizing mutations. Recognizing that highly concentrated neutral mutations interfere with data set quality, we have explored three protein stability data sets: S2648, PON-tstab, and the symmetric S that differ in size and quality. A characteristic leptokurtic shape in the ΔΔ distributions of all three data sets including the curated and symmetric ones was reported due to concentrated neutral mutations.

Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells.

Background: Senescent cells accumulate in tissues over time as part of the natural ageing process and the removal of senescent cells has shown promise for alleviating many different age-related diseases in mice. Cancer is an age-associated disease and there are numerous mechanisms driving cellular senescence in cancer that can be detrimental to recovery. Thus, it would be beneficial to develop a senolytic that acts not only on ageing cells but also senescent cancer cells to prevent cancer recurrence or progression.

Bridging the Bridging Imidazolate in the Bimetallic Center of the Cu/Zn SOD1 and ALS.

Metallation status of human Cu/Zn superoxide dismutase 1 (SOD1) plays a pivotal role in the pathogenesis of amyotrophic lateral sclerosis (ALS). All of the amino acids found in the bimetallic center have been associated with ALS except for two positions. H63 which forms the bridging imidazolate ion in the bimetallic center and K136 which is not directly involved in coordination but located in the bimetallic center were not reported to be mutated in any of the identified ALS cases.

Lipase and Water in a Deep Eutectic Solvent: Molecular Dynamics and Experimental Studies of the Effects of Water-In-Deep Eutectic Solvents on Lipase Stability.

Given the accumulated evidence on the effects of water-in-deep eutectic solvents (DESs) on the solvent nanostructure and the yield of lipase reactions, here we have used molecular dynamics (MD) simulations to delineate the structure and dynamics of thermoalkalophilic lipases in choline chloride/urea-based DES (reline) with varying hydration levels. Results indicated that pure reline almost froze the lipase backbone, while hydrated reline that showed a less ordered nanostructure than the pure form introduced some fluctuations to lipase structures, particularly to the lid domain. Although none of the solvents led to unfolding, solvation by 8 M urea or water when accompanied with elevated temperature caused the most significant loss of secondary structure.

Understanding thermal and organic solvent stability of thermoalkalophilic lipases: insights from computational predictions and experiments.

Bacillus thermocatenulatus lipase (BTL2), a member of the isolated lipase family known as thermoalkalophilic lipases, carries potential for industrial applications owing to its ability to catalyze versatile reactions under extreme conditions. This study investigates the molecular effects of distinct solvents on the stability of BTL2 at different temperatures, aiming to contribute to lipase use in industrial applications. Initially, molecular dynamic (MD) simulations were carried out to address for the molecular impacts of distinct solvents on the structural stability of BTL2 at different temperatures.

Translation and cross-cultural adaptation of the extended version of the Nordic musculoskeletal questionnaire into Turkish.

Objectives: The purpose of this study was to translate and culturally adapt the Extended Version of the Nordic Musculoskeletal Questionnaire (NMQ-E) for use in Turkey.

Methods: The cross-cultural adaptation was achieved by translating the items from the original version, with back-translation performed by independent mother-tongue translators, followed by committee review. Reliability (internal consistency and test-retest) was examined for 132 students (97 females, 35 males; mean±SD age: 19.

Comprehensive evaluation of the MM-GBSA method on bromodomain-inhibitor sets.

MM-PB/GBSA methods represent a higher-level scoring theory than docking. This study reports an extensive testing of different MM-GBSA scoring schemes on two bromodomain (BRD) datasets. The first set is composed of 24 BRPF1 complexes, and the second one is a nonredundant set constructed from the PDBbind and composed of 28 diverse BRD complexes.

Comparative Assessment of Seven Docking Programs on a Nonredundant Metalloprotein Subset of the PDBbind Refined.

Extensive usage of molecular docking for computer-aided drug discovery resulted in development of numerous programs with versatile scoring and posing algorithms. Selection of the docking program among these vast number of options is central to the outcome of drug discovery. To this end, comparative assessment studies of docking offer valuable insights into the selection of the optimal tool.

Insights into an alternative benzofuran binding mode and novel scaffolds of polyketide synthase 13 inhibitors.

Small molecules targeting biosynthesis of mycolic acids in the tuberculosis causing bacterium carry high potential for anti-tuberculosis drug discovery. Hitherto, benzofuran containing molecules were identified to target the thioesterase domain of polyketide synthase 13 (Pks13), one of the crucial constituents of this pathway. Among these, TAM16 was also reported to be highly potent in vivo.

In silico identification of inhibitors targeting N-Terminal domain of human Replication Protein A.

Replication Protein A (RPA) mediates DNA Damage Response (DDR) pathways through protein-protein interactions (PPIs). Targeting the PPIs formed between RPA and other DNA Damage Response (DDR) mediators has become an intriguing area of research for cancer drug discovery. A number of studies applied different methods ranging from high throughput screening approaches to fragment-based drug design tools to discover RPA inhibitors.

Thermostability of the PYL-PP2C Heterodimer Is Dependent on Magnesium: In Silico Insights into the Link between Heat Stress Response and Magnesium Deficiency in Plants.

Magnesium deficiency increases the susceptibility of plants toward heat stress. The correlation between magnesium levels and stress response has been studied at the physiological level; albeit, the molecular explanation to this relationship remains elusive. Among diverse pathways implicated in the heat stress, the abscisic acid (ABA) signal modulates the heat stress response by magnesium dependent phosphatases (PP2Cs).

Predicting the impact of mutations on the specific activity of Bacillus thermocatenulatus lipase using a combined approach of docking and molecular dynamics.

Lipases are important biocatalysts owing to their ability to catalyze diverse reactions with exceptional substrate specificities. A combined docking and molecular dynamics (MD) approach was applied to study the chain-length selectivity of Bacillus thermocatenulatus lipase (BTL2) towards its natural substrates (triacylglycerols). A scoring function including electrostatic, van der Waals (vdW) and desolvation energies along with conformational entropy was developed to predict the impact of mutation.

Probing the roles of two tryptophans surrounding the unique zinc coordination site in lipase family I.5.

A unique zinc domain found in all of the identified members of the lipase family I.5 is surrounded by two conserved tryptophans (W61 and W212). In this study, we investigated the role of these hydrophobic residues in thermostability and thermoactivity of the lipase from Bacillus thermocatenulatus (BTL2) taken as the representative of the family.

Zinc Modulates Self-Assembly of Bacillus thermocatenulatus Lipase.

Thermoalkalophilic lipases are prone to aggregation from their dimer interface to which structural zinc is very closely located. Structural zinc sites have been shown to induce protein aggregation, but the interaction between zinc and aggregation tendency in thermoalkalophilic lipases remains elusive. Here we delineate the interplay between zinc and aggregation of the lipase from Bacillus thermocatenulatus (BTL2), which is taken to be a representative of thermoalkalophilic lipase.

Direct in vitro selection of titanium-binding epidermal growth factor.

Epidermal growth factor (EGF) with affinity to TiO2 surfaces was obtained by direct in vitro selection. A random peptide library was generated for fusion to the N-terminal of EGF, and polypeptides exhibiting affinity were selected in vitro by ribosome display. The best-performing polypeptide sequence was selected for synthesis using a solid-phase method and showed high affinity to TiO2 after refolding.